Dihydropyridine derivatives

ABSTRACT

Dihydropyridine derivatives of the formula ##STR1## wherein the symbols R and R 1  to R 6  have the significance given in claim 1, have a pronounced calcium-antagonist activity and can accordingly be used as medicaments, especially in the control or prevention of angina pectoris, ischemia, high blood pressure and/or migraine. The compounds of formula I can be prepared by reacting an ylidene compound of the formula ##STR2## with an enamine of the formula ##STR3##

BRIEF SUMMARY OF THE INVENTION

The invention relates to dihydropyridine derivatives. In particular, itrelates to dihydropyridine derivatives of the formula ##STR4## wherein Ris aryl or a heterocyclic residue with up to three hetero atoms selectedfrom oxygen, nitrogen and sulfur. R¹ and R³ each independently, is C₁-C₄ -alkyl or C₃ -C₆ -cycloalkyl, R² is hydrogen or C₁ -C₄ -alkyl, R⁴ isC₁ -C₆ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₆ -cycloalkyl, C₃-C₆ -cycloalkyl-C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl, halo-C₂ -C₆ -alkyl,hydroxy-C₂ -C₆ -alkyl, ω,ω,ω-trifluoro-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₆-alkoxycarbonyl-C₂ -C₆ -alkyl, C₁ -C₄ -alkanoyloxy-C₁ -C₆ -alkyl, C₃ -C₆-alkenyloxy-C₁ -C₆ -alkyl, C₁ -C₆ -alkylthio-C₁ -C₆ -alkyl, benzyloxy-C₁-C₆ -alkyl, phenyl optionally substituted by halogen, cyano, di-C₁ -C₆-alkylamino, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl, trifluoromethyl or nitro, R⁵is hydrogen, C₁ -C₆ -alkyl or C₃ -C₆ -cycloalkyl, R⁶ is C₁ -C₆ -alkyl,C₃ -C₆ -cycloalkyl, C₃ -C₆ -cycloalkyl-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₆-alkylthio-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxycarbonyl-C₂ -C₆ -alkyl or R⁵ andR⁶ taken together are the group --CH₂ CH₂ --O--CH₂ CH₂ -- or a--(CH₂)_(n) -- group in which n is an integer of 2 to 7, in the form ofstereoisomers, diastereoisomeric mixtures, racemates and opticalantipodes.

The compounds of formula I are useful in the control or prevention ofillnesses or in the improvement of health, especially in the control orprevention of angina pectoris, ischemia, high blood pressure andmigraine.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to dihydropyridine derivatives. In particular, itrelates to dihydropyridine derivatives of the formula ##STR5## wherein Ris aryl or a heterocyclic residue with up to three hetero atoms selectedfrom oxygen, nitrogen and sulfur, R¹ and R³ each independently, is C₁-C₄ -alkyl or C₃ -C₆ -cycloalkyl, R² is hydrogen or C₁ -C₄ -alkyl, R⁴ isC₁ -C₆ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₃ -C₆ -cycloalkyl, C₃-C₆ -cycloalkyl-C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl, halo-C₂ -C₆ -alkyl,hydroxy-C₂ -C₆ -alkyl, ω,ω,ω-trifluoro-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₆-alkoxycarbonyl-C₂ -C₆ -alkyl, C₁ -C₄ -alkanoyloxy-C₁ -C₆ -alkyl, C₃ -C₆-alkenyloxy-C₁ -C₆ -alkyl, C₁ -C₆ -alkylthio-C₁ -C₆ -alkyl, benzyloxy-C₁-C₆ -alkyl, phenyl optionally substituted by halogen, cyano, di-C₁ -C₆-alkylamino, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl, trifluoromethyl or nitro orphenyl-C₁ -C₆ -alkyl optionally substituted by halogen, cyano, di-C₁ -C₆-alkylamino, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl, trifluoromethyl or nitro, R⁵is hydrogen, C₁ -C₆ -alkyl or C₃ -C₆ -cycloalkyl, R⁶ is C₁ -C₆ -alkyl,C₃ -C₆ -cycloalkyl, C₃ -C₆ -cycloalkyl-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₆-alkylthio-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxycarbonyl-C₂ -C₆ -alkyl or R⁵ andR⁶ taken together are the group --CH₂ CH₂ --O--CH₂ CH₂ -- or a--(CH₂)_(n) -- group in which n is an integer of 2 to 7,

in the form of stereoisomers, diastereoisomeric mixtures, racemates andoptical antipodes.

The compounds of formula I are distinguished by valuable pharmacodynamicproperties.

Objects of the present invention comprise compounds of formula I per seand for use as therapeutically active substances, the preparation ofthese compounds, intermediates for the preparation of these compounds,medicaments containing these compounds and the preparation of suchmedicaments, as well as the use of compounds of formula I in the controlor prevention of illnesses or in the improvement of health, especiallyin the control or prevention of angina pectoris, ischemia, high bloodpressure and migraine.

The term "alkyl" as used in the present description-alone or incombination-denotes straight-chain and branched, saturated hydrocarbonresidues with the number of carbon atoms given in the respective case,such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.-butyl, tert.-butyl and the like. The term "alkoxy" denotes alkylether groups in which the term "alkyl" has the above significance. Theterm "C₃ -C₆ -alkenyl" denotes straight-chain and branched hydrocarbongroups with 3-6 carbon atoms in which at least one carbon-carbon bond isunsaturated, such as allyl, butenyl and the like. The term "C₃ -C₆-alkenyloxy" denotes alkenyl ether groups in which the term "C₃ -C₆-alkynyl" denotes straight-chain and branched hydrocarbn groups with 3-6carbon atoms in which at least one carbon-carbon triple bond is present,such as propargyl and the like. The term "C₃ -C₆ -cycloalkyl" denotescyclic, saturated hydrocarbon residues with 3-6 carbon atoms, such ascyclopropyl, cyclohexyl and the like. The term "C₁ -C₄ -alkanoyloxy"denotes the acyloxy residue of an alkanecarboxylic acid with 1-4 carbonatoms, such as, formyloxy, acetoxy, propionyloxy, butyryloxy and thelike. The term "halogen" denotes the four halogen atoms fluorine,chlorine, bromine and iodine. The term "aryl" denotes a mono- orbicyclic aromatic hydrocarbon residue with up to 10 carbon atoms in thearomatic ring structure which is optionally mono-, di- ortri-substituted by phenyl, C₁ -C₆ -alkyl, C₃ -C₆ -alkenyl, C₃ -C₆-alkynyl, C₁ -C₆ -alkoxy, halogen. trifluoromethyl, trifluoromethoxy,difluoromethoxy, trifluoromethylthio, difluoromethylthio, nitro, cyano,azido, C₁ -C₆ -alkoxycarbonyl, aminocarbonyl, aminosulfonyl, C₁ -C₆-alkylthio, C₁ -C₆ -alkylsulfonyl or C₁ -C₆ -alkanoyl or which isoptionally disubstituted by C₃ -C₅ -alkylene or dioxy-C₁ -C₂ -alkylene,such as, chlorophenyl, tolyl, α,α,α-trifluorotolyl, dichlorophenyl,chloronitrophenyl, naphthyl and the like. The term "heterocyclicresidue" embraces 5- and 6-membered mono- and bicyclic, heterocycleswhich are optionally mono-, di- or tri-substituted by phenyl, C₁ -C₆-alkyl, C₃ -C₆ -alkenyl, C₃ -C₆ -alkynyl, C₁ -C₆ -alkoxy, halogen,trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio,difluoromethylthio, nitro, cyano, azido, C₁ -C₆ -alkoxycarbonyl,aminocarbonyl, aminosulfonyl, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulfonylor C₁ -C₆ -alkanoyl or which are optionally disubstituted by C₃ -C₅-alkylene or dioxy-C₁ -C₂ -alkylene, such as, thienyl, furyl, pyrryl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridyl, N-oxidopyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl,isoquinolyl, indolyl, benzimidazolyl, quinazolyl, quinoxalyl,(2,1,3-benzoxadiazol)-4-yl, ( 2,1,3-benzothiadiazol)-4-yl, benzofuranyl,benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, indazolyl and the like. The term "C₁ -C₆ -alkanoyl"denotes the acyl residue of an alkanecarboxylic acid with 1-6 carbonatoms, such as, formyl, acetyl, propionyl, butyryl and the like.

A preferred class of compounds of formula I comprises those in which R⁴is C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl, halo-C₂ -C₆ -alkyl, hydroxy-C₂-C₆ -alkyl, ω,ω,ω-trifluoro-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl,C₁ -C₄ -alkanoyloxy-C₁ -C₆ -alkyl, benzyloxy-C₁ -C₆ -alkyl or phenyl-C₁-C₆ -alkyl optionally substituted by halogen, R⁵ is C₁ -C₆ -alkyl, R⁶ isC₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl or C₁ -C₆ -alkoxycarbonyl-C₂-C₆ -alkyl or R⁵ and R⁶ taken together are a --(CH₂)_(n) -- group inwhich n is an integer of 2 to 7 and R is naphthyl, phenyl optionallymonosubstituted by C₁ -C₆ -alkyl, halogen, trifluoromethyl or nitro oroptionally disubstituted by halogen or halogen and nitro, imidazolyl orpyridyl.

A more preferred class of compounds of formula I comprises those inwhich R is aryl, preferably phenyl substituted by C₁ -C₆ -alkyl,halogen, trifluoromethyl or nitro and especially 3-nitro-phenyl,2-chloro-5-nitropehnyl or 2,5-dichlorophenyl. R¹ preferably is methyl.The preferred significance of R² is hydrogen. R³ preferably is C₁ -C₄-alkyl, especially methyl. Further, still more preferred compounds offormula I are those in which R⁴ is C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl,halo-C₂ -C₆ -alkyl, hydroxy-C₂ -C₆ -alkyl, ω,ω,ω-trifluoro-C₁ -C₆-alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₄ -alkanoyloxy-C₁ -C₆ -alkyl,benzyloxy-C₁ -C₆ -alkyl or phenyl-C₁ -C₆ -alkyl optionally substitutedby halogen, preferably C₁ -C₆ -alkyl, ω,ω,ω-trifluoro-C₁ -C₆ -alkyl, C₁-C₆ -alkoxy-C₁ -C₆ -alkyl or phenyl-C₁ -C₆ -alkyl, especially methyl,isopropyl, 2,2,2 -trifluoroethyl, 2-propoxyethyl or 1-phenylethyl. R⁵preferably is C₁ -C₆ -alkyl, especially methyl, ethyl or isopropyl. Thepreferred significance of R⁶ is C₁ -C₆ -alkyl or C₁ -C₆ -alkoxy-C₁ -C₆-alkyl, especially methyl, ethyl, isopropyl, butyl or methoxyethyl.

From the above it follows that there are particularly preferred thosecompounds of formula I in which R signifies 3-nitrophenyl,2-chloro-5-nitrophenyl or 2,5-dichlorophenyl, R¹ and R³ each is methyl,R² is hydrogen, R⁴ is methyl, isopropyl, 2,2,2-trifluoroethyl,2-propoxyethyl or 1-phenylethyl, R⁵ is methyl, ethyl or isopropyl and R⁶is methyl, ethyl, isopropyl, butyl or methoxyethyl.

The most preferred group of compounds of formula I comprises those inwhich R is 3-nitrophenyl, R¹ and R³ each is methyl, R² is hydrogen, R⁴is isopropyl or 2-propoxyethyl, R⁵ is methyl and R⁶ is methyl, butyl ormethoxyethyl.

The most preferred compounds of formula I are:

5-(Dimethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester.

5-(butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester and

1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester.

The compounds of formula I can be prepared in accordance with theinvention by reacting an ylidene compounds of the formula ##STR6##wherein R, R¹, R⁵ and R⁶ are as previously described, with an enamine ofthe formula ##STR7## wherein R², R³ and R⁴ are as previously described,and, if desired, separating a stereoisomeric mixture obtained into itsstereoisomers.

The reaction of an ylidene compound of formula II with an enamine offormula III is carried out according to known methods in the presence ofan acid such as p-toluenesulfonic acid or DL-camphor-10-sulfonic acid orthe H⁺ form of a cation exchanger such as, for example, Amberlyst® 15 inan inert solvent or solvent mixture at a temperature between about 20°and 150° C., preferably at the reflux temperature of the solvent orsolvent mixture. Suitable solvents for this purpose are, for example,alcohols such as methanol, ethanol or isopropanol, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether orglycol dimethyl ether, dimethylformamide, dimethyl sulfoxide oracetonitrile. Although the pressure is not critical and the reaction canbe carried out readily at elevated pressure, for reasons of conveniencethe reaction is preferably carried out at normal atmospheric pressure.The two starting materials are preferably used in equimolar amounts.

The ylidene compounds of formula II form part of the invention. They canbe prepared from ketosulfonamides of the formula ##STR8## wherein R¹, R⁵and R⁶ are as previously described, by reaction with an aldehyde of theformula

    RCHO                                                       V

wherein R is as previously decribed. The reaction is carried outaccording to known methods under water-cleaving conditions, for exampleby heating to reflux in an inert organic solvent such as an aromatichydrocarbon, for example, benzene or toluene, and the azeotropic removalof the water which is formed. The ketosulfonamides of formula IV areknown or can be prepared in an analogous manner to that described in theliterature.

The aldehydes of formula V above are known or can be obtained in ananalogous manner to the preparation of the known compounds.

The compounds of formula I contain at least one asymmetric center(4-position) and can therefore exist as optical antipodes or asracemates. Compounds of formula I which contain more than one asymmetriccenter can exist in various diastereoisomeric forms. The prsentinvention embraces all possible stereoisomers of compounds of formula Iand all possible diastereoisomeric mixtures and racemates, as well asthe separation of these diastereoisomeric mixtures which can be carriedout according to known methods.

The compounds of formula I have a pronounced therapeuticcalcium-antagonist activity and can accordingly be used as medicaments,especially for the control or prevention of angina pectoris, ischemia,high blood pressure and migraine.

The calcium-antagonist activity as well as the blood pressure-loweringproperties of the compounds in accordance with the invention can bedemonstrated in the tests described hereinafter:

A. ³ H-Nifedipine binding determination:

The determination is carried out on homogenates or on partially-cleanedmembranes of rabbit or guinea pig heart. The reaction mixture (0.3 ml)consists of 0.2-0.8 mg of membrane protein, 1 nM of ³ H-nifedipine (or0.25 nM of ³ H-nitrendipine) and various concentrations of the testsubstance. The incubation lasts 30 minutes at 25° C. or 37° C. and isstopped by dilution with the incubation buffer; a filtration issubsequently carried out. The filter-bound radioactivity is measuredwith a scintillation counter. Specific binding, that is, receptor-bound,is defined as the difference between total and unspecific-boundradioactivity. The unspecific binding is determined in the presence ofan excess of non-radioactive nifedipine (1 μM).

The activity (potency) of a compound in this test is defined by the IC₅₀and %maximum inhibition values (%max. inhibition). The IC₅₀ is thesubstance concentration (in mol/l) which produces a half-maximuminhibition of the specific ³ H-nifedipine (or ³ H-nitrendipine) binding.The maximum inhibition of the specific binding is given by the %maximuminhibition value; this value is established as 100% for the referencecompound nifedipine. Both parameters are extrapolated from aconcentration-binding curve.

B. Haemodynamic parameters in the narcotized dog:

The 4 most important measurement parameters (with respective measurementunits) of the haemodynamic experiment are: (1) CBF: Coronary Blood Flow(in ml/min)--the velocity of blood flow through the coronary arteries;(2) HR: heart rate (in beats/min)--the heart frequency; (3) BP: bloodpressure (in mm Hg)--the blood pressure; and (4) dp/dt: rate of increasein left ventricular pressure (in mm Hg/sec)--the rate of increase of theleft ventricular pressure, as a measurement of the contractility forceof the heart. The values are given as the %maximum variation from theinitial value (Δ%) and the duration of this variation (t) per dosageadministered.

There is thus obtained not only an overall picture of the activity ofthe substance, but also an estimation as to the potential selectivityfor a specific part of the circulatory system in the entire organism.After the administration of an anaesthetic, the dog is intubated andrespired artificially. Blood pH, pCO₂, pO₂ and haemoglobin are measuredhourly with a blood-gas analyzer. The blood pressure (systolic anddiastolic) is measured with a probe in the aorta abdominalis. The heartfrequency is recorded by means of a tachometer, which is disengaged fromthe pressure pulse. For the other measurements the heart must firstly beopened in order that a probe can be inserted in the left ventricle(heart chamber) for the pressure measurements (dp/dt). The coronaryblood flow is measured with a flowing probe in the left coronary artery(descendens).

The results obtained in these tests are compiled in the following Table:

                                      TABLE                                       __________________________________________________________________________    A               B                                                                   IC.sub.50                                                                          % max.                                                                             CBF  HR    Bp    dp/dt  Dosage                                Compound                                                                            [M]  inhib.                                                                             ml/min. t                                                                          beats/min. t                                                                        mm Hg t                                                                             mm Hg/sec. t                                                                         mg/kg. p.o.                           __________________________________________________________________________    A     4.4 · 10.sup.-9                                                           100  50 (60')                                                                           -19 (40')                                                                           -55 (60')                                                                           -42 (60')                                                                            0.03                                  B     9.5 · 10.sup.-9                                                           100  78 (40')                                                                           -11 (>30')                                                                          -30 (24')                                                                           -2 (20')                                                                             0.03                                  C     9.0 · 10.sup.-9                                                           100  108 (20')                                                                          -11 (>60')                                                                          -32 (>60')                                                                          -16 (>60')                                                                           0.03                                  __________________________________________________________________________     A =                                                                           5(Dimethylsulphamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinic     acid 2propoxyethyl ester                                                      B =                                                                           5(Butylmethylsulphamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicoti    ic acid isopropyl ester                                                        C =                                                                           1,4Dihydro-2,6-dimethyl-5-[(2methoxyethyl)methylsulphamoyl4-(3-nitropheny    )nicotinic acid isopropyl ester                                           

The compounds of formula I can be used as medicaments, for example, inthe form of pharmaceutical preparations. The pharmaceutical preparationscan be administered orally, for example, in the form of tablets, coatedtablets, dragees, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The administration can, however, also be carried outrectally, for example, in the form of suppositories, or parenterally,for example, in the form of injection solutions.

For the preparation of tablets, coated tablets, dragees and hardgelatine capsules the compounds of formula I can be processed withpharmaceutically inert, inorganic or organic excipients. As suchexcipients there can be used, for example, for tablets, dragees and hardgelatine capsules, lactose, maize starch or derivatives thereof, talc,stearic acid or its salts or the like.

For soft gelatine capsules, there are suitable as excipients, forexample, vegetable oils, waxes, fats, semi-solid, liquid polyols and thelike.

For the preparation of solutions and syrups, suitable as excipients are,for example, water, polyols, saccharose, invert sugar, glucose and thelike.

For injection solutions, suitable as excipients are, for example, water,alcohols, polyols, glycerine, vegetable oils and the like.

For suppositories, suitable as excipients are, for example, natural orhardened oils, waxes, fats, semi-liquid, liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizing agents, wetting agents, emulsifying agents,sweetening agents, coloring agents, flavoring agents, salts for varyingthe osmotic pressure, buffers, coating agents or antioxidants. They canalso contain still other therapeutically valuable substances.

In accordance with the invention, compounds of formula I can be used inthe control or prevention of angina pectoris, ischemia, high bloodpressure and migraine. The dosage can vary within wide limits and will,of course, be adjusted to the individual requirements in each particularcase. In general, in the case of oral administration a daily dosage ofabout 10 to 100 mg of a compound of formula I should be appropriate,whereby, however, the upper limit just given can also be exceeded whenthis is shown to be indicated.

The following Examples further illustrate the invention. Alltemperatures are given in degrees Celsius, unless otherwise stated.

EXAMPLE 1

A solution of 3.0 g (0.001 mol) ofα-acetyl-N,N-dimethyl-3-nitrostyrenesulfonamide and 1.43 g (0.01 mol) of3-aminocrotonic acid isopropyl ester in 30 ml of isopropanol is heatedto reflux for 2 hours, thereupon treated with 1.16 g (0.005 mol) ofDL-camphor-10-sulfonic acid and then heated to reflux for an additional15 minutes. After concentration under reduced pressure, the oily residueis partitioned between water and methylene chloride, the organic phaseis washed with a saturated aqueous solution of sodium chloride, driedover sodium sulfate and concentrated to dryness. The residual yellow oilis chromatographed on 350 g of silica gel with methylene chloride/ethylacetate (9:1) as the elution agent. The homogeneous fractions yield anoil which crystallizes upon trituration with ether. Afterrecrystallization from methylene chloride/ether, there are obtained 3.2g (75.5%) of5-(dimethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-nicotinicacid isopropyl ester, m.p. 136°-138°, as a yellowish crystalline powder.

The α-acetyl-N,N-dimethyl-3-nitrostyrenesulfonamide used as the startingmaterial can be prepared as follows:

A solution of 20 g (0.16 mol) of N,N-dimethylmethanesulfonamide in 200ml of dry tetrahydrofuran is treated dropwise under argon firstly at15°-20° with 100 ml (0.16 mol) of a 1.6 molar n-butyl lithium solutionin hexane and then at 10°-15° with a solution of 14.5 g (0.08 mol) ofacetic acid 4-nitrophenyl ester in 40 ml of dry tetrahydrofuran. Thetemperature is then allowed to rise to room temperature (about 30minutes) and the mixture is stirred for an additional 30 minutes. Afterconcentration under reduced pressure the black residue is partitionedbetween 350 ml of ice-water and 150 ml of ether. The aqueous phase isacidified with 100 ml of 2N hydrochloric acid and extracted withmethylene chloride. The extracts, dried over sodium sulfate, are thenevaporated to dryness. The residual oil is chromatographed on 500 g ofsilica gel with toluene/ethyl acetate (4:1) as the elution agent. Theuniform fractions yield 10.2 g (38%) ofN,N-dimethyl-2-oxopropanesulfonamide as an oil which can be used for thenext step without further purification. The oil crystallizes slowly uponstanding. For the analysis, a sample is sublimed in a high vacuum,whereby colorless crystals, m.p. 47°-49° are obtained.

A solution of 4.1 g (0.025 mol) of N,N-dimethyl-2-oxopropanesulfonamideand 3.8 g (0.025 mol) of 3-nitrobenzaldehyde in 25 ml of benzene istreated with 0.1 ml of piperidine and 0.3 ml of glacial acetic acid andthe mixture is thereupon heated to reflux for 1 hour with the separationof water. The reaction solution is then concentrated to dryness underreduced pressure, the residue is dissolved in 20 ml of toluene and thesolution obtained is again evaporated to dryness. The residual oil ischromatographed on 170 g of silica gel with methylene chloride as theelution agent. The uniform fractions yield 4.3 g (58%) ofα-acetyl-N,N-dimethyl-3-nitrostyrenesulfonamide, m.p. 115°-120°, as acolorless crystalline powder.

EXAMPLE 2

The following compounds were obtained in an analogous manner to thatdescribed in Example 1:

5-(Dimethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid methyl ester, m.p. 166°-169°, fromα-acetyl-N,N-dimethyl-3-nitrostyrenesulfonamide and 3-aminocrotonic acidmethyl ester;

5-(dimethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester, m.p. 74°-77°, fromα-acetyl-N,N-dimethyl-3-nitrostyrenesulfonamide and 3-aminocrotonic acid2-propoxyethyl ester;

5-(butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester, m.p. 80°-83°, fromα-acetyl-N-butyl-N-methyl-3-nitrostyrenesulfonamide and 3-aminocrotonicacid isopropyl ester;

5-(diethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester, m.p. 133°-136°, fromα-acetyl-N,N-diethyl-3-nitrostyrenesulfonamide and 3-aminocrotonic acidisopropyl ester;

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(1-pyrrolidinylsulfonyl)nicotinicacid isorpopyl ester, m.p. 169°-172°, from4-(3-nitrophenyl)-3-(1-pyrrolidinylsulfonyl)-3-buten-2-one and3-aminocrotonic acid isopropyl ester, and

1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester, m.p. 86°-88°, fromα-acetyl-N-(2-methoxyethyl)-N-methyl-3-nitrostyrenesulfonamide and3-aminocrotonic acid isopropyl ester.

The following 3-nitrostyrenesulfonamides used as starting materials werealso prepared in an analogous manner to that described in Example 1:

α-Acetyl-N-butyl-N-methyl-3-nitrostyrenesulfonamide in the form of athick oil;

α-acetyl-N,N-diethyl-3-nitrostyrenesulfonamide, m.p. 112°-115°;

4-(3-nitrophenyl)-3-(1-pyrrolidinylsulfonyl)-3-buten-2-one, m.p.123°-126°, and

α-acetyl-N-(2-methoxyethyl)-N-methyl-3-nitrostyrenesulfonamide, m.p.86°-88°.

EXAMPLE 3

A solution of 3.12 g (0.01 mol) ofα-acetyl-N-isopropyl-3-nitrostyrenesulfonamide in 30 ml of isopropanolis treated with 1.87 g (0.01 mol) of 3-aminocrotonic acid 2-propoyxethylester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acid inaccordance with the procedure described in Example 1. Afterchromatography on silica gel with methylene chloride/ethyl acetate (4:1)as the elution agent the crude product is recrystallized fromisopropanol. There is obtained 1.0 g (21%) of5-(isopropylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester, m.p. 155°-158°, as a colorless crystallinepowder.

The α-acetyl-N-isopropyl-3-nitrostyrenesulfonamide used as the startingmaterial can be prepared as follows:

A solution of 16.8 g (0.16 mol) of N-isopropylmethanesulfonamide in 200ml of dry tetrahydrofuran is treated with 200 ml (0.32 mol) of a 1.6molar n-butyl lithium solution in hexane and 14.5 g (0.08 mol) of aceticacid 4-nitrophenyl ester in 40 ml of dry tetrahydrofuran in accordancewith the procedure described in Example 1. The crude produce ischromatographed on 1000 g of silica gel with methylene chloride/ethylacetate (9:1) as the elution agent. The homogeneous fraction yield 7.5 gof N-isopropyl-2-oxopropanesulfonamide as an oil which can be used forthe next step without further purification.

A solution of 7.5 g (about 0.04 mol) ofN-isopropyl-2-oxopropanesulfonamide and 6.0 g (0.04 mol) of3-nitrobenzaldehyde in 40 ml of benzene is treated with 0.16 ml ofpiperidine and 0.48 ml of glacial acetic acid in an analogous manner tothat described in Example 1. The oily crude product is triturated withether, whereby crystallization occurs. There are obtained 2.5 g ofα-acetyl-N-isopropyl-3-nitrostyrenesulfonamide in the form of colorlesscrystals, m.p. 153°-157°.

EXAMPLE 4

A solution of 3.67 g (0.01 mol) ofα-(cyclohexylcarbonyl)-N,N-dimethyl-3-nitrostyrenesulfonamide in 30 mlof isopropanol is treated with 1.15 g (0.01 mol) of 3-aminocrotonic acidmethyl ester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acid inaccordance with the procedure described in Example 1. Afterchromatography on silica gel with methylene chloride/ethyl acetate (9:1)as the elution agent the crude product is recrystallized fromacetonitrile. There are obtained 1.5 g (32%) of6-cyclohexyl-5-(dimethylsulfamoyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)nicotinicacid methyl ester, m.p. 185°-188°, as a colorless crystalline powder.

The α-(cyclohexylcarbonyl)-N,N-dimethyl-3-nitrostyrenesulfonamide usedas the starting material is prepared from 5.8 g (0.025 mol) of2-cyclohexyl-N,N-dimethyl-2-oxoethanesulfonamide and 3.8 g (0.025 mol)of 3-nitrobenzaldehyde in an analogous manner to that described inExample 1. After chromatography on silica gel with methylene chloride asthe elution agent, there are obtained 5.9 g (66%) ofα-(cyclohexylcarbonyl)-N,N-dimethyl-3-nitrostyrenesulfonamide in theform of colorless crystals, m.p. 115°-118°.

EXAMPLE 5

A solution of 4.27 g (0.01 mol) of6-(α-acetyl-N-methyl-3-nitrostyrenesulfonamido)caproic acid ethyl esterin 30 ml of ethanol is treated with 1.15 g (0.01 mol) of 3-aminocrotonicacid methyl ester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acidanalogously to Example 1. After chromatography on silica gel withmethylene chloride/ethyl acetate (9:1) as the elution agent the crudeproduct is recrystallized from methylene chloride/ether. There areobtained 3.4 g (65%) of5-{[5-(ethoxycarbonyl)pentyl]methylsulfamoyl}-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid methyl ester, m.p. 83°-86°, as a colorless crystalline powder.

The 6-(α-acetyl-N-methyl-3-nitrostyrenesulfonamido)caproic acid ethylester used as the starting material can be prepared as follows:

A solution of 72.7 g (0.4 mol) of 6-aminocaproic acid methyl esterhydrochloride in 2000 ml of methylene chloride is treated at 20°-25°firstly with 140 ml (1.0 mol) of triethylamine and then with a solutionof 38 ml (0.48 mol) of methanesulfochloride in 160 ml of methylenechloride. The mixture is subsequently stirred at room temperature for 90minutes and thereupon treated with 800 ml of 0.5N hydrochloric acid. Theorganic phase is washed with saturated aqueous solutions of sodiumbicarbonate and sodium chloride and dried over sodium sulfate. Afterconcentration under reduced pressure the residual oil is dissolved in400 ml of dimethylformamide, treated at 15°-20° with a solution of 0.48mol of sodium methylate (from 11.0 g of sodium) in 100 ml of methanoland thereupon stirred at room temperature for 30 minutes. The methanolis then distilled off at 50° under reduced pressure and the residualsolution is treated at 15°-20° with a solution of 48 ml (0.8 mol) ofmethyl iodide in 100 ml of dimethylformamide. The reaction mixture isthen stirred at room temperature for an additional 15 minutes andthereupon concentrated to dryness under reduced pressure. The residue ispartitioned between water and methylene chloride and the organic phaseis washed with a saturated aqueous sodium chloride solution, dried oversodium sulfate and evaporated to dryness. There are obtained 90 g (95%)of 6-[(methylsulfonyl)methylamino]caproic acid methyl ester as an oilwhich can be used for the next step without further purification.

A mixture of 90 g (0.38 mol) of 6-[(methylsulfonyl)methylamino]caproicacid methyl ester and 67.5 g (0.76 mol) of 2-amino-2-methyl-1-propanolis stirred at 135° for 16 hours. The reaction mixture is partitionedbetween 500 ml of methylene chloride and 250 ml of 2N hydrochloric acidand the organic phase is washed with a saturated aqueous sodium chloridesolution, dried over sodium sulfate and concentrated to dryness. Theresidual oil crystallizes upon trituration with ether. There areobtained 85.2 g (76%) ofN-(2-hydroxy-1,1-dimethylethyl)-6-[(methylsulfonyl)methylamino]capronamide,m.p. 77°-80°, as a colorless crystal powder. For analysis, a sample isrecrystallized from ethyl acetate, m.p. 84°-87°.

A solution of 82.5 g (0.28 mol) ofN-(2-hydroxy-1,1-dimethylethyl)-6-[(methylsulfonyl)methylamino]capronamidein 525 ml of methylene chloride is treated at a temperature between -5°and 0° with a solution of 46.5 ml (0.64 mol) of thionyl chloride in 175ml of methylene chloride. Thereupon, the temperature is allowed to riseto 20° within 15 minutes. The solution is stirred at room temperaturefor an additional 45 minutes and thereafter again cooled to 0°. Thereaction mixture is then treated at 0°-5° with a solution of 220 g ofpotassium carbonate in 880 ml of water and thereupon stirred for anadditional 15 minutes without cooling. The organic phase is then washedwith a saturated aqueous sodium chloride solution, dried over sodiumsulfate and concentrated to dryness. The residual oil is chromatographedon 1000 g of silica gel with ethyl acetate/ethanol (9:1) as the elutionagent. The homogeneous fractions yield 62.2 g (80%) of4.5-dihydro-4,4-dimethyl-2-{5-[(methylsulfonyl)methylamino]pentyl}-oxazoleas a yellow oil.

A solution of 22.1 g (0.08 mol) of4,5-dihydro-4,4-dimethyl-2-{5-[(methylsulfonyl)methylamino]pentyl}-oxazolein 100 ml of dry tetrahydrofuran is treated with 0.08 mol of butyllithium and 7.25 g (0.04 mol) of acetic acid 4-nitrophenyl ester inaccordance with the procedure described in Example 1. Afterconcentration under reduced pressure, the residue is partitioned betweenwater and ether, the aqueous phase is acidified with 80 ml of 2Nhydrochloric acid and extracted with methylene chloride. The aqueoussolution is then adjusted to pH 7 with 2N sodium hydroxide solution andagain extracted with methylene chloride. The extracts, dried over sodiumsulfate, are then evaporated to dryness. The residue is chromatographedon 250 g of silica gel with ethyl acetate/ethanol (9:1) as the elutionagent. There are obtained 7 g of4,5-dihydro-4,4-dimethyl-2-{5-[(2-oxopropylsulfonyl)-methylamino]pentyl}oxazoleas an oil which still contains about 30% of the starting oxazole inaccordance with NMR data.

This oil (7.0 g) is dissolved in a mixture of 70 ml of ethanol and 2.5ml of sulfuric acid and the resulting solution is heated to reflux for12 hours. The reaction mixture is then poured on to 140 ml of ice-waterand extracted with methylene chloride. The organic extracts arecombined, washed with saturated aqueous sodium chloride solution anddried over sodium sulfate. After concentration under reduce pressure,the oily residue is chromatogrpahed on 150 g of silica gel with ethylacetate/ethanol (9:1) as the elution agent. There are obtained 6.5 g of6-[(2-oxopropylsulfonyl)methylamino]caproic acid ethyl ester as an oilwhich contains about 30% of 6-[(methylsulfonyl)methylamino]caproic acidethyl ester in accordance with NMR data.

This mixture (6.5 g) is treated with 3.0 g (0.02 mol) of3-nitrobenzaldehyde, 0.08 ml of piperidine and 0.24 ml of glacial aceticacid in 20 ml of benzene in an analogous manner to that described inExample 1. The oily crude product is chromatographed on 250 g of silicagel firstly with methylene chloride and then with methylenechloride/ethyl acetate (9:1) as the elution agent. The uniform fractionsyield an oil which crystallizes upon trituration with ether. There areobtained 5.35 g of6-(α-acetyl-N-methyl-3-nitrostyrenesulfonamido)caproic acid ethyl esterin form of colorless crystals, m.p. 60°-63°.

EXAMPLE 6

A solution of 3.42 g (0.01 mol) ofα-acetyl-N-(2-methoxyethyl)-N-methyl-3-nitrostyrenesulfonamide and 1.87g (0.01 mol) of 3-aminocrotonic acid 2-propoxyethyl ester in 15 ml ofisopropanol is heated to reflux for 2 hours, thereupon treated with 1.0g of Amberlyst® 15 as the catalyst and then heated to reflux for anadditional 30 minutes. After concentration under reduced pressure theoily residue is dissolved in methylene chloride, the catalyst remainingbehind is removed by filtration under suction, and the filtrate iswashed with a saturated aqueous sodium chloride solution, dried oversodium sulfate and concentrated to dryness. The residual oil ischromatographed on 300 g of silica gel with methylene chloride/ethylacetate (4:1) as the elution agent. The uniform fractions yield an oilwhich crystallizes upon trituration and leaving to stand under hexane.After recrystallization from ether, there are obtained 2.4 g (47%) of1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester, m.p. 67°-70°, as an almost colorlesscrystalline powder.

EXAMPLE 7

The following compounds were prepared in an analogous manner to thatdescribed in Example 6:

4-(3-Chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]nicotinicacid isopropyl ester, m.p. 76°-79°, fromα-acetyl-3-chloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide and3-aminocrotonic acid isopropyl ester;

4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]nicotinicacid 2-propoxyethyl ester, m.p. 83°-85°, fromα-acetyl-3-chloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide and3-aminocrotonic acid 2-propoxyethyl ester;

4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]nicotinicacid isopropyl ester, m.p. 134°-136°, fromα-acetyl-2,3-dichloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide and3-aminocrotonic acid isopropyl ester;

1,4-dihydro-5-dimethylsulfamoyl-2,6-dimethyl-4-(2-trifluoromethylphenyl)nicotinicacid methyl ester, m.p. 205°-208°, fromα-acetyl-N,N-dimethyl-2-trifluoromethylstyrenesulfonamide and3-aminocrotonic acid methyl ester;

4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]nicotinicacid isopropyl ester, m.p. 107°-110°, fromα-acetyl-2-chloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide and3-aminocrotonic acid isoprorpyl ester;

5-(butylmethylsulfamoyl)-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethylnicotinicacid isopropyl ester, m.p. 98°-101°, fromα-acetyl-2-chloro-N-butyl-N-methylstyrenesulfonamide and 3-aminocrotonicacid isopropyl ester;

5-(butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid cyclopropylmethyl ester, m.p. 93°-96°, fromα-acetyl-N-butyl-N-methyl-3-nitrostyrenesulfonamide and 3-aminocrotonicacid cyclopropylmethyl ester, and

5-(butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)nicotinicacid isopropyl ester, m.p. 119°-122°, fromN-butyl-N-methyl-2-oxo-1-(2-pyridylmethylene)propanesulfonamide and3-aminocrotonic acid isopropyl ester.

The following styrenesulfonamides used as starting materials wereprepared in a manner analogous to that described in Example 1:

α-Acetyl-3-chloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide in theform of a thick oil;

α-acetyl-2,3-dichloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide,m.p. 55°-58°;

α-acetyl-N,N-dimethyl-2-trifluoromethylstyrenesulfonamide in the form ofa thick oil;

α-acetyl-2-chloro-N-(2-methoxyethyl)-N-methylstyrenesulfonamide, m.p.76°-79°;

α-acetyl-2-chloro-N-butyl-N-methylstyrenesulfonamide, m.p. 65°-67°, and

N-butyl-N-methyl-2-oxo-1-(2-pyridylmethylene)propanesulfonamide, m.p.59°-61°.

EXAMPLE A

Preparation of tablets of the following composition:

    ______________________________________                                        I.    5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-                                                             20.0    mg                                            dimethyl-4-(3-nitrophenyl)nicotinic acid                                      isopropyl ester, micronized                                                   Lactose powder          40.0    mg                                            Maize starch white      24.9    mg                                      II.   Dioctyl sodium sulfosuccinate                                                                         0.1     mg                                            Maize starch white      5.0     mg                                            Water                   q.s                                             III.  Maize starch white      6.0     mg                                      IV.   Talc                    3.0     mg                                            Magnesium stearate      1.0     mg                                                                    100.0   mg                                      ______________________________________                                    

The substances of phase I are sieved and mixed. This mixture ismoistened with the maize starch paste II and kneaded. The moist mass isgranulated, dried and converted into a suitable particle size. Phase IIIis admixed. This mixture is mixed with phase IV for a short time.

The ready-to-press mixture is pressed into tablets of 100 mg with abreak-bar.

EXAMPLE B

Preparation of tablets of the following composition:

    ______________________________________                                        I.    5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-                                                             200.0   mg                                            dimethyl-4-(3-nitrophenyl)nicotinic acid                                      isopropyl ester                                                               Lactose powder          42.9    mg                                            Maize starch white      50.0    mg                                      II.   Dioctyl sodium sulfosuccinate                                                                         0.1     mg                                            Maize starch white      20.0    mg                                            Water                   q.s                                             III.  Maize starch white      30.0    mg                                      IV.   Talc                    3.5     mg                                            Magnesium stearate      3.5     mg                                                                    350.0   mg                                      ______________________________________                                    

The substances of phase I are sieved and mixed. This mixture ismoistened with the maize starch paste II and kneaded. The moist mass isgranulated, dried and converted into a suitable particle size. Phase IIIis admixed. This mixture is mxed with phase IV for a short time.

The ready-to-press mass is pressed into tablets of 350 mg with abreak-bar.

EXAMPLE C

Preparation of capsules of the following composition:

    ______________________________________                                        I.    5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-                                                             20.0    mg                                            dimethyl-4-(3-nitrophenyl)nicotinic acid                                      isopropyl ester, micronized                                                   Lactose powder          48.0    mg                                      II.   Maize starch            5.0     mg                                            Water                   q.s.                                            III.  Lactose crystalline     50.0    mg                                            Maize starch            15.0    mg                                      IV.   Talc                    10.0    mg                                            Magnesium stearate      2.0     mg                                                                    150.0   mg                                      ______________________________________                                    

The substances of phase I are sieved and mixed. This mixture ismoistened with the maize starch paste II and kneaded. The moist mass isgranulated, dried and converted into a suitable particle size. Phase IIIis admixed. This mixture is mixed with phase IV for a short time.

The capsule mixture is filled into size 2 capsules each containing 150mg.

EXAMPLE D

An aqueous drop suspension of the following composition is prepared:

    ______________________________________                                                              5 mg per 1 ml                                           ______________________________________                                        5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-                                                             0.05      g                                           dimethyl-4-(3-nitrophenyl)nicotinic acid                                      isopropyl ester                                                               Sodium benzoate         0.035     g                                           Saccharin sodium        0.015     g                                           Acrylic acid polymerizate                                                                             0.1-1.0   g                                           Saccharose              3.5       g                                           Citric acid             0.025     g                                           Polyoxyethylene stearate                                                                              0.002-0.01                                                                              g                                           Sodium hydroxide        q.s                                                   Flavor                  q.s                                                   Food coloring           q.s                                                   Water deionized         ad 10.0   ml                                          ______________________________________                                    

EXAMPLE E

When the procedures described in Examples A-D are followed, tablets,capsules and injection preparations can be prepared from the following,likewise preferred compounds:

5-(Dimethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester and

1,4-dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester.

We claim:
 1. A compound of the formula ##STR9## wherein R is naphthyl orphenyl optionally monosubstituted by C₁ -C₆ -alkyl, halogen,trifluoromethyl or nitro or optionally disubstituted by halogen orhalogen and nitro; imidazolyl; or pyridyl, R¹ and R³ each,independently, is C₁ -C₆ -alkyl or C₃ -C₆ -cycloalkyl, R² is hydrogen orC₁ -C₆ -alkyl, R⁴ is C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl, halo-C₂ -C₆-alkyl, hydroxy-C₂ -C₆ -alkyl, ω, ω, ω-trifluoro-C₁ -C₆ -alkyl, C₂ -C₆-alkoxy-C₁ -C₆ -alkyl, C₁ C4-alkanoyloxy-C₁ -C₆ -alkyl, benzyloxy-C₁ -C₆-alkyl, or phenyl-C₁ -C₆ -alkyl optionally substituted by halogen, R⁵ ishydrogen, or C₁ -C₆ -alkyl, R⁶ is C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆-alkyl, C₁ -C₆ -alkoxy-carbonyl-C₂ -C₆ -alkyl or R⁵ and R⁶ takentogether the group --CH₂ CH₂ --O--CH₂ CH₂ -- or a --(CH2)n-- group inwhich n is an integer of 2 to 7,as a stereoisomer, diastereoisomericmixture, racemate or optical antipode.
 2. A compound, in accordance withclaim 1, wherein R is naphthyl or phenyl optionally monosubstituted byC₁ -C₆ -alkyl, halogen, trifluoromethyl or nitro or optionallydisubstituted by halogen or halogen and nitro; imidazolyl; or pyridyl,R¹ is methyl, R₂ is hydrogen and R³ is C₁ -C4-alkyl.
 3. A compound, inaccordance with claim 2, wherein R⁴ is C₁ -C₆ -alkyl, cyano-C₂ -C₆-alkyl, halo-C₂ -C₆ -alkyl, hydroxy-C₂ -C₆ -alkyl, ω,ω,ω-trifluoro-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₄ -alkanoyloxy-C₁ -C₆-alkyl, benzyloxy-C₁ -C₆ -alkyl or phenyl-C₁ -C₆ -alkyl optionallysubstituted by halogen. R⁵ is C₁ -C₆ -alkyl, and R⁶ is C₁ -C₆ -alkyl orC₁ -C₆ -alkoxy-C₁ -C₆ -alkyl.
 4. A compound, in accordance with claim 3,whrein R is 3-nitrophenyl, 2-chloro-5-nitrophenyl or 2,5-dichlorophenyl,R¹ and R³ each, independently, is methyl, R² is hydrogen, R⁴ is methyl,isopropyl, 2,2,2-trifluoroehtyl, 2-propoxyethyl or 1-phenylethyl, R⁵ ismethyl, ethyl or isopropyl and R⁶ is methyl, ethyl, isopropyl, butyl ormethoxyethyl.
 5. A compound, in accordance with claim 4, wherein R is3-nitrophenyl, R¹ and R³ each is methyl, R² is hydrogen, R⁴ is isopropylor 2-propoxyethyl, R⁵ is methyl and R⁶ is methyl, butyl or methoxyethyl.6. A compound, in accordance with claim 1,5[-(Dimethylsulflamoyl)]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester.
 7. A compound, in accordance with claim 1,5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester.
 8. A compound, in accordance with claim 1,1,4-Dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester.
 9. A pharmaceutical composition for administrationto a host requiring a calcium-antagonist which comprises an effectiveamount of a compound of the formula ##STR10## wherein R is naphthyl orphenyl optionally monosubstituted by C₁ -C₆ -alkyl, halogen,trifluoromethyl or nitro or optionally disubstituted by halogen orhalogen and nitro; imidazolyl; or pyridyl, R¹ and R³ each, independentlyis C₁ -C₆ -alkyl or C₃ -C₆ -cycloalkyl, R² is hydrogen or C₁ -C₆ -alkyl,R⁴ is C₁ -C₆ -alkyl, cyano-C₂ -C₆ -alkyl, halo-C₂ -C₆ -alkyl, hydroxy-C₂-C₆ -alkyl, ω, ω, ω-trifluoro-C₁ -C₆ -alkyl, C₂ -C₆ -alkoxy-C₁ -C₆-alkyl, C₁ -C₄ -alkanoyloxy-C₁ -C₆ -alkyl, benzyloxy-C₁ -C₆ -alkyl, orphenyl-C₁ -C₆ -alkyl optionally substituted by halogen, R⁵ is hydrogen,or C₁ -C₆ -alkyl, R⁶ is C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁-C₆ -alkoxycarbonyl-C₂ -C₆ -alkyl or R⁵ and R⁶ taken together the group--CH₂ CH₂ --O--CH₂ CH₂ -- or a --(CH₂)_(n) -- group in which n is aninteger of 2 to 7,as a stereoisomer, diastereoisomeric mixture, racemateor optical antipode and an inert carrier.
 10. A pharmaceuticalcomposition, in accordance with claim 9, wherein R is 3-nitrophenyl,2-chloro-5-nitrophenyl or 2,5-dichlorophenyl, R¹ and R³ each,independently, is methyl, R² is hydrogen, R⁴ is methyl, osopropyl,2,2,2-trifluoroethyl, 2-propoxyethyl or 1-phenylethyl, R⁵ is methyl,ethyl or isopropyl and R⁶ is methyl, ethyl, isopropyl, butyl ormethoxyethyl.
 11. A pharmaceutical composition, in accordance with claim10, wherein R is 3-nitrophenyl, R¹ and R³ each is methyl, R² ishydrogen, R⁴ isopropyl or 2-propoxyethyl, R⁵ is methyl and R⁶ is methyl,butyl or methoxyethyl.
 12. A pharmaceutical composition, in accordancewith claim 9, wherein the compound of formula I is5-[(Dimethylsulfamoyl)]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester.
 13. A pharmaceutical composition, inaccordance with claim 9, wherein the compound of formula I is5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester.
 14. A pharmaceutical composition, in accordancewith claim 9, wherein the compound of formula I is1,4-Dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester.
 15. A method of administering to host requiring acalcium-antagonist, an effective amount of a compound of the formula##STR11## wherein R is naphthyl or phenyl optionally monosubstituted byC₁ -C₆ -alkyl, halogen, trifluoromethyl or nitro or optionallydisubstituted by halogen or halogen and nitro; imidazolyl; or pyridyl,R¹ and R³ each, independently, is C₁ -C₆ -alkyl or C₃ -C₆ -cycloalkyl,R² is hydrogen or C₁ -C₆ -alkyl, R⁴ is C₁ -C₆ -alkyl, cyano-C₂ -C₆-alkyl, halo-C₂ -C₆ -alkyl, hydroxy-C₂ -C₆ -alkyl, ω, ω, ω-trifluoro-C₁-C₆ -alkyl, C₂ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C4-alkanoyloxy-C₁ -C₆alkyl, benzyloxy-C₁ -C₆ -alkyl, or phenyl-C₁ -C₆ -alkyl optionallysubstituted by halogen, R⁵ is hydrogen, or C₁ -C₆ -alkyl, R⁶ is C₁ -C₆-alkyl, C₁ -C₆ -alkoxy-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxycarbonyl-C₂ -C₆-alkyl or R⁵ and R⁶ taken together the group --CH₂ CH₂ --O--CH₂ CH₂ --or a --(CH2)n-- group in which n is an integer of 2 to 7,as astereoisomer, diastereoisomeric mixture, racemate or optical antipode.16. A method, in accordance with claim 15, wherein R is 3-nitrophenyl,2-chloro-5-nitrophenyl or 2,5-dichlorophenyl, R¹ and R³ each,independently, is methyl, R² is hydrogen, R⁴ is methyl, isopropyl,2,2,2-trifluoroethyl, 2-propoxyethyl or 1-phenylethyl, R⁵ is methyl,ethyl or isopropyl and R⁶ is methyl, ethyl, isopropyl, butyl ormethoxyethyl.
 17. A method, in accordance with claim 16, wherein R is3-nitrophenyl, R¹ and R³ each is methyl, R² is hydrogen, R⁴ is isopropylor 2-propoxyethyl, R⁵ is methyl and R⁶ is methyl, butyl or methoxyethyl.18. A method, in accordance with claim 15, wherein the compound offormula I is5-[(Dimethylsulfamoyl)]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid 2-propoxyethyl ester.
 19. A method, in accordance with claim 15,wherein the compound of formula I is5-(Butylmethylsulfamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinicacid isopropyl ester.
 20. A method, in accordance with claim 15, whereinthe compound of formula I is1,4-Dihydro-2,6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinicacid isopropyl ester.